Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][S:14][C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[C:24]([O:25][CH3:26])=[CH:23][C:21]([NH2:22])=[C:20]([CH3:27])[CH:19]=1.Cl.N1C=CC=CC=1>P(Cl)(Cl)(Cl)=O.CN(C)C=O>[Cl:17][C:18]1[C:24]([O:25][CH3:26])=[CH:23][C:21]([NH:22][C:13]2[S:14][C:8]3[C:9]([N:12]=2)=[CH:10][C:11]2[CH:2]=[C:3]([C:15]#[N:16])[CH:4]=[N:5][C:6]=2[CH:7]=3)=[C:20]([CH3:27])[CH:19]=1
Reactant: N#Cc1cnc2cc3scnc3cc2c1O
Reactant: COc1cc(N)c(C)cc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2nc3cc4cc(C#N)cnc4cc3s2)c(C)cc1Cl
Yield: 15.5 %

Procedure:
To a mixture of 100 mg (0.44 mmol) of 8-hydroxy[1,3]thiazolo[4,5-g]quinoline-7-carbonitrile in 5 mL of phosphoryl chloride is added five drops of N,N-dimethylformamide. The mixture is heated at reflux temperature for 30 minutes and then concentrated in vacuo. To the residue at 0° C. is added 50 mL of water. The solids are collected, washed with water, and dried in vacuo. To a mixture of this compound in 2 mL of 2-ethoxyethanol are added 76 mg (0.44 mmol) of 4-chloro-5-methoxy-2-methylaniline and 20 mg of pyridine hydrochloride. The mixture is refluxed for one hour and concentrated. The residue is chromatographed by silica gel chromatography, eluting with 9:1 methylene chloride/methanol to yield 26 mg (16%) of product as a dark oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].Cl[CH2:12][CH:13]=O.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]2[N:6]([CH:12]=[CH:13][N:9]=2)[C:7]=1[CH3:8]
Reactant: O=CCCl
Reactant: Cc1cc(N)nc(C)c1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc2nccn2c(C)c1Br
Temperature: 25 °C

Procedure:
5-Bromo-4,6-dimethyl-pyridin-2-ylamine (1.51 g, 7.5 mmol) and chloroacetaldehyde (0.95 ml, 50% in water, 7.5 mmol) were mixed with toluene (12 ml). The mixture was heated to reflux for 3 h, upon which time a dark solid residue appeared at the bottom of the reaction flask. After cooling down to rt, NaHCO3 (20 ml, sat. aq.) and CH2Cl2 (20 ml) were added. Layers were separated and the aqueous layer was further extracted with CH2Cl2 (20 ml×2). The combined CH2Cl2 was dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (CH2Cl2/CH3OH, 18:1) to give the 6-bromo-5,7-dimethyl-imidazo[1,2-a]pyridine as a yellow oil (985 mg, 58%, contaminated with some starting material).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]([OH:36])[CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CI.[C:42]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]([O:36][CH3:42])[CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(C(=O)NC2CCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C(=O)NC2CCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cc1OC
Reaction time: 16 h

Procedure:
To a mixture of methyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)-2-hydroxybenzoate (100 mg, 0.18 mmol) in 2 mL of DMF were added MeI (38 mg, 0.27 mmol) and K2CO3 (37 mg, 0.27 mmol) at room temperature, and then the mixture was stirred for 16 hours. The mixture was poured into water and extracted with EtOAc (3×5 mL). The organic layer was washed with 0.1 N HCl (5 mL) and brine. The organic layer was dried over Na2SO4. After filtration and concentration, the crude methyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)-2-methoxybenzoate was obtained and used the next step without purification (80 mg, 78%). LC-MS: 565 [M+H]+, tR=1.48 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=O.C1C=CC=CC=1>C(O)(=O)C>[CH2:19]([O:18][C:12](=[O:17])[CH:13]=[C:14]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1)[CH3:16])[CH3:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(N)cc1OC
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C=C(C)Nc1ccc(OC)c(OC)c1

Procedure:
4-Aminoveratrole (62.0 g.), ethyl acetoacetate (63.0 g.), benzene (375 ml.), and acetic acid (2.1 ml.) are combined and refluxed in a flask equipped with a Dean-Stark trap to remove water until thin layer chromatography indicated the reaction is complete. The solvent is removed under reduced pressure to give a dark oil which crystallized upon standing. Recrystallization from hexane gives 79.0 g. of a tan powder, m.p. 59°-60°; a second crop afforded 6.7 g., m.p. 54°-56°. A sample is recrystallized from ethanol/water to give an analytical sample, m.p. 57°-58°.
Reaction SMILES: C(OO)(=[O:3])C.[C:6]([NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[C:11]=1[CH3:17])(=[O:8])[CH3:7]>C(O)(=O)C>[C:6]([NH:9][C:10]1[CH:15]=[CH:14][N+:13]([O-:3])=[C:12]([CH3:16])[C:11]=1[CH3:17])(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1ccnc(C)c1C
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: CC(=O)Nc1cc[n+]([O-])c(C)c1C
Temperature: 50 °C
Reaction time: 12 h

Procedure:
200 mL 30% peracetic acid in acetic acid was slowly added to a solution of 50 g 4-acetylamino-2,3-dimethylpyridine in 100 mL glacial acetic acid at 60° C. The solution was held at 70° C. for 12 hours then reduced under vacuum heated by a 50° C. water bath. Yield, 58 g N-oxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([O:23]CC)=O)[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][N:30]([CH3:35])[S:31]([CH3:34])(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:27][CH2:28][CH2:29][N:30]([CH3:35])[S:31]([CH3:34])(=[O:33])=[O:32])=[O:23])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: CN(CCN)S(C)(=O)=O
Product: CN(CCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O)S(C)(=O)=O
Yield: 92.7 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.056 mmol) described in example 92 and N-(2-aminoethyl)-N-methylmethanesulfonamide (55 mg, 0.364 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-N-{2[methyl(methylsulfonyl)amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (24 mg, 96% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.39 (br s, 1 H), 8.55 (s, 1 H), 7.38 (s, 1 H), 7.16-7.12 (m, 2 H), 7.03-6.99 (m, 2 H), 4.12 (s, 2 H), 3.68-3.63 (m, 2 H), 3.56 (s, 3 H), 3.42-3.38 (m, 2 H), 2.94 (s, 3 H), 2.82 (s, 3 H). HRMS m/z calcd for C21H24N4O5FS: 463.1451; Found: 463.1443.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][N:18]4[C:26]([C:29](=[O:34])C(Cl)(Cl)Cl)=[CH:27][CH:28]=[C:17]4[CH2:16]3)=[O:14])=[CH:9][C:8]=2[S:35]([NH2:38])(=[O:37])=[O:36])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1.O>O1CCOCC1>[OH2:4].[NH2:38][S:35]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:13]([N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][N:18]2[C:26]([C:29]([NH:39][CH2:40][C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)=[O:34])=[CH:27][CH:28]=[C:17]2[CH2:16]1)=[O:14])(=[O:37])=[O:36].[NH2:38][S:35]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:13]([N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][N:18]2[C:26]([C:29]([NH:39][CH2:40][C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)=[O:34])=[CH:27][CH:28]=[C:17]2[CH2:16]1)=[O:14])(=[O:37])=[O:36]
Reactant: NCc1cccnc1
Reactant: NS(=O)(=O)c1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1N1CCOCC1
Solvent: O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1N1CCOCC1
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution containing 0.83 g (0.0014 mol) of 2-morpholin-4-yl-5-{[3-(trichloroacetyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}benzenesulfonamide of Step C and 0.30 g (0.0028 mol) of 3-aminomethylpyridine in 25 mL of 1,4-dioxane was stirred under reflux overnight. The reaction mixture was allowed to cool to room temperature and poured into 200 mL of water. The beige solid that precipitated was collected and washed with water to provide the title compound (0.35 g), m.p. 159-161° C.
Reaction SMILES: Cl.[N:2]12C[CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[OH:12])C1)[CH2:9]2.[O:13]1C2(CCC(=O)CC2)O[CH2:15][CH2:14]1.CC1C=CC(S(C[N+]#[C-])(=O)=O)=CC=1>>[O:12]1[C:5]2([CH2:4][CH2:10][CH:8]([C:9]#[N:2])[CH2:7][CH2:6]2)[O:13][CH2:14][CH2:15]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: OC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Product: N#CC1CCC2(CC1)OCCO2

Procedure:
U.S. Pat. No. 8,314,119 shows synthesis of (4s)-1-azaadamantan-4-ol HCl salt from a 7-step process of: (1) Reducing of 1,4-dioxaspiro[4.5]decan-8-one with TOSMIC giving 1,4-dioxaspiro[4.5]decane-8-carbonitrile; (2) Reducing resulting product with LAH giving 1,4-dioxaspiro[4.5]decan-8-ylmethanamine; (3) Cyclizing resulting product with a double-Mannich type condensation using paraformaldehyde and sulfuric acid to form azaadamantan-4-one; (4) Reducing ketone group of azaadamantan-4-one to an alcohol using NaBH4 in presence of borane-THF complex to form a diastereomeric mixture of 1-azaadamantan-4-ol N-borane complex; (5) Coupling resulting product with 4-chlorobenzoic acid; (6) Separating (4s) isomer by column chromatography (silica gel, using 3:1 hexanes-EtOAc), followed by removing 4-chlorobenzoic acid moiety with NaOH; and (7) Removing BH3 group with HCl giving (4s)-1-azaadamantan-4-ol HCl salt. U.S. Pat. No. 8,314,119 is incorporated herein by reference.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:21]1C2C(=CC(B(O)O)=CC=2)[CH:23]=[CH:22]1>>[NH:21]1[C:4]2[C:5](=[CH:6][C:1]([C:7]3[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=3[C:14]=45)=[CH:2][CH:3]=2)[CH:23]=[CH:22]1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1ccc2[nH]ccc2c1
Product: O=C1NCCc2c(-c3ccc4[nH]ccc4c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (530 mg, 2.00 mmol) and indole-5-boronic acid (354 mg, 2.20 mmol) were coupled to yield 2-(1H-indol-5-yl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 396 mg (66%) as a beige solid: m.p. 315-317° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 3.10 (m, 2H), 3.41 (m, 2H), 6.54 (m, 1H), 7.17 (t, J=7.8 Hz, 1H), 7.42 (m, 2H), 7.55 (m, 2H), 7.68 (d, J=7.5 Hz, 1H), 7.83 (br s, 1H), 8.05 (br t, 1H), 11.26 (br s, 1H), 11.48 (br s, 1H). MS (electrospray, MH+) 302. Anal. (C19H15N3O.0.25 H2O) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:39])([F:38])[C:13]([CH2:33][NH:34][CH2:35][CH2:36][CH3:37])([OH:32])[CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:34]([CH2:35][CH2:36][CH3:37])[CH2:33][C:13]([OH:32])([CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:12]([F:38])([F:11])[F:39])=[O:6]
Reactant: O=C(O)c1ccccc1F
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1F

Procedure:
Prepared similarly to Example 11 from 2-fluorobenzoic acid and 1,1,1-trifluoro-3-[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: Cl.NC[C:4]1[CH:5]=[C:6]([OH:14])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9].[CH:15]([N:18](CC)C(C)C)(C)C.C1(=O)N(O[C:30](=[O:44])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])C(=O)CC1>CN(C)C=O>[C:40]([O:39][C:37]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30]([NH:18][CH2:15][O:14][C:6]1[C:7](=[CH:12][CH:13]=[CH:4][CH:5]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:44])=[O:38])([CH3:41])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(CN)cc1O
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1OCNC(=O)CCCCCNC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 80 %

Procedure:
Methyl 4-aminomethylsalicylate hydrochloride (2.25 g, 10.3 mmoles) was suspended in anhydrous N,N-dimethylformamide (30 mL), and N,N-diisopropylethylamine (3.6 mL, 20.7 mmoles) was added, followed by N-tert-butoxycarbonyl-6-aminohexanoic acid succinimidyl ester (3.38 g, 10.3 mmoles). The mixture was stirred under dry nitrogen for 18 hours, during which time all solids dissolved. The solvent was then evaporated to leave a light brown syrup, which was partitioned between ethyl acetate (100 mL) and 1M aqueous hydrochloric acid (100 mL). The layers were separated, and the ethyl acetate solution was washed with saturated aqueous sodium bicarbonate (100 mL) and saturated aqueous sodium chloride (100 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and evaporated to an amorphous off-white solid. The solid was crystallized form ethyl acetate/hexanes, filtered, and dried in vacuo to afford 3.25 g (80% yield) of methyl (N-tert-butoxycarbonyl-6-aminohexanoyl)aminomethylsalicylate (m.p. 120°-121° C., open capillary, uncorrected).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[N:11]=[C:12]1[NH:16][CH2:15][CH2:14][N:13]1[OH:17].[CH:18]1(C)[CH2:23]CC(C(C)C)C(N(C2C(C(C)C)CCC(C)C2)C=O)[CH2:19]1.C(Br)C#C>>[ClH:3].[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=1[N:11]=[C:12]1[NH:16][CH2:15][CH2:14][N:13]1[O:17][CH2:23][C:18]#[CH:19]
Reactant: CC1CCC(C(C)C)C(N(C=O)C2CC(C)CCC2C(C)C)C1
Reactant: ON1CCNC1=Nc1c(Cl)cccc1Cl
Agent: C#CCBr
Agent: [H-]
Agent: [Na+]
Product: C#CCON1CCNC1=Nc1c(Cl)cccc1Cl
Product: Cl
Reaction time: 0.5 h

Procedure:
1.31 g. of sodium hydride (55% strength suspension) are added to a solution of 6.15 g. of 2-[(2,6-dichlorophenyl)imino]-1-hydroxyimidazolidine in 45 ml. of absolute dimenthylformamide at a temperature of 25°. After 30 minutes, 4.16 g. of propargyl bromide are added dropwise. After 30 minutes, the mixture is poured onto 500 ml. of a saturated solution of sodium chloride and the aqueous phase is extracted with ether. The ether extracts are washed with aqueous hydrochloric acid. The aqueous extracts are then rendered basic with 3 N caustic soda solution and extracted with ether. After evaporating off the solvent, the residue is dissolved in ether, and hydrogen chloride in dioxane is added. The residue is recrystallized from methanol/acetonitrile, whereupon 2-[(2,6-dichlorophenyl)imino]-1-(2-propynyloxy)-imidazolidine hydrochloride, m.p. 198°-199° (from methanol/acetonitrile) is obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:19][CH2:18][N:17](C(OCC)=O)[CH2:16][CH2:15]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([O:29]CC)=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(N3CCN(C(=O)OCC)CC3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCNCC3)c(F)cc2c1=O

Procedure:
A suspension of 0.7 g (1.6 mmole) of ethyl 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[4- (ethoxycarbonyl)-1-piperazinyl]-1,8-naphthyridine-3carboxylate, 6 ml of 10% aqueous sodium hydroxide and 2 ml of ethanol was refluxed for three hours. The reaction was filtered through a fiber glass pad to clarify and acidified to pH 1.5 with 6.0 M hydrochloric acid and lyophilized. The residue was dissolved in 10 ml of ammonium hydroxide and the solution concentrated in vacuo. The precipitate which formed was removed by filtration, washed with aqueous ethanol, ether, and dried in vacuo to give 0.04 g, mp 274°-276° C.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH3:28]C(C)([O-])C.[K+].[Si:34]([O:51][CH2:52][C@@H:53]1[C@@H:60]2[C@@H:56]([O:57]C(O)[CH2:59]2)[CH2:55][C@@H:54]1[F:62])([C:47]([CH3:50])([CH3:49])[CH3:48])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.OS([O-])(=O)=O.[K+]>C1COCC1>[Si:34]([O:51][CH2:52][C@H:53]1[C@@H:54]([F:62])[CH2:55][C@H:56]([OH:57])[C@@H:60]1[CH2:59]/[CH:28]=[CH:8]\[CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])([C:47]([CH3:50])([CH3:49])[CH3:48])([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1[C@H]2CC(O)O[C@H]2C[C@@H]1F)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@@H]1F)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 98 %

Procedure:
4-Carboxybutyltriphenylphosphonium bromide (55.81 g, 126.0 mmol) was suspended in anhydrous THF (1.5 L) and potassium t-butoxide (252 mL, 252 mmol) was added dropwise at room temperature. After the addition was complete, the orange ylide was cooled to 0° C. and (3aR,4S,5S,6aS)-4-((tert-butyldiphenylsilyloxy)methyl)-5-fluorohexahydro-2H-cyclopenta[b]furan-2-ol (prepared in Step B, 26 g, 63 mmol) as a solution in THF was added dropwise. The reaction mixture was allowed to slowly warm to room temperature overnight with stirring. The reaction was acidified with 5% KHSO4, extracted with ethyl acetate, and washed twice with brine. The crude material was dried over sodium sulfate, filtered and evaporated to an oil. The crude product was purified on silica gel, eluted with hexanes-ethyl acetate (4:1 with 0.4% acetic acid) to afford the title intermediate (30.8 g, 97%).
Reaction SMILES: Cl[C:2]([C:4]1[C:5]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[N:6][C:7]([CH3:14])=[N:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[CH2:3].N12CCCN=C1CCCCC2.O>CS(C)=O>[C:2]([C:4]1[C:5]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[N:6][C:7]([CH3:14])=[N:8][C:9]=1[C:10]([F:11])([F:13])[F:12])#[CH:3]
Reactant: C=C(Cl)c1c(-n2ccnc2)nc(C)nc1C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CS(C)=O
Product: C#Cc1c(-n2ccnc2)nc(C)nc1C(F)(F)F
Yield: 63 %

Procedure:
5-(1-Chlorovinyl)-4-imidazol-1-yl-2-methyl-6-trifluoromethyl-pyrimidine (0.20 g) was dissolved in dimethylsulfoxide (2 ml) and 1,8-diazabicyclo-[5,4,0]-undec-7-ene (0.11 g) was added at room temperature with stirring. The mixture was stirred for 2 hr in room temperature and then added water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-THF) to give 5-Ethynyl-4-imidazol-1-yl-2-methyl-6-trifluoromethylpyrimidine (0.11 g) as colorless crystalline solid, mp 121-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([S:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17]C)=[O:16])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.[OH-].[Na+].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([S:12]([C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([OH:17])=[O:16])=[O:31])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccccc1Sc1cc(Cl)ccc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)c1ccccc1S(=O)c1cc(Cl)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
Dimethyl 4-chloro-2,2'-thiodibenzoate (6.72 g) was dissolved in methylene chloride. To the solution was added m-chloroperbenzoic acid (4 g) and the solution was stirred at room temperature for 6 hours. The reaction mixture was poured into a 10% aqueous sodium hydroxide solution and extracted with methylene chloride. The methylene chloride extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and the filtrate was evaporated to give a product. The product was suspended into a 20% aqueous sodium hydroxide solution and heated at 60° C. for 3 hours. After cooling, the solution was acidified with 6N HCl to give a precipitate. Recrystallization from aqueous methanol gave 4-chloro-2,2'-sulfinyldibenzoic acid (compound No. 25) in an amount of 4.5 g (yield: 70%). m.p. 279-281° C.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:19][OH:20])[C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1F)[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>O1CCCC1>[CH2:1]([C@@H:8]1[C@@H:9]([OH:10])[C:11]2[C:16](=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[O:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@H](Cc1ccccc1)[C@@H](O)c1ccc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O[C@H]1c2ccc(Br)cc2OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (1R, 2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol (prepared from 33.5 kg (54.8 moles) of [4R-[3(2R, 3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one, 1-methyl-2-pyrrolidinone solvate without isolation) in 185 L of tetrahydrofuran was added 12.9 kg (115 mol) of potassium tert-butoxide. The reaction mixture was heated at reflux for 4 hours at which point the reaction was found to be complete by thin layer chromatography (hexanes/ethyl acetate, 3:1). The reaction mixture was cooled to ambient temperature, quenched with 170 L of water, diluted with 83 L of ethyl acetate, and acidified to pH 5.3 (aqueous layer) with 7.5 L of concentrated hydrochloric acid. The organic layer was concentrated under vacuum to approximately 38 L of a slurry, diluted with 76 L of isopropyl ether, warmed to dissolve the solids, slowly cooled to 0° C., and granulated at 0° C. for 12 hours. (3S, 4R)-3-Benzyl-7-bromo-chroman-4-ol, 5.1 kg of white solid, was isolated by filtration. The mother liquor was washed with 4 L of saturated aqueous sodium chloride, concentrated to a final volume of 57 L, and granulated at 0° C. for 12 hours affording a 4.3 kg second crop of (3S, 4R)-3-benzyl-7-bromo-chroman-4-ol.